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(MRC DTP) New strategies for immuno-PET radiochemistry

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  • Full or part time
    Dr A McMahon
    Dr M Fairclough
    Prof K Williams
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Aims:
To enhance immunoPET availability through:
1. Significant reduction in antibody usage.
2. Development of a secondary [18F]affibody approach applicable to all mAbs.
3. Validation of both methods
1) Parsimonious Radiochemistry:
Immuno-PET combines the sensitivity of Positron Emission Tomography (PET) with the high target affinity of antibodies, directly applicable in the emerging field of immuno-oncology. The current ‘gold standard’ technique utilises 89Zr radiolabelled monoclonal antibodies (mAbs) for immuno-PET[1, 2]. However the current radiosynthetic methods require large amounts of mAbs, which can be prohibitively expensive. A second drawback are the slow pharmacokinetics of mAbs necessitates the use of longer lived PET radioisotopes which result in a higher patient radiation dose.
The Wolfson Molecular Imaging Centre has considerable expertise in radiolabelling mAbs with 89Zr, and routinely produces 89Zr-mAbs for preclinical studies. We will further develop 89Zr radiolabelling techniques using automated microfluidic and sold phase chemistry methods to enable the use of much smaller amounts of starting mAb. Scaling down the radiosynthesis and automation of the method will permit the development of an accessible library of 89Zr-mAbs for preclinical imaging a variety of different targets. Automation will yield a robust 89Zr-mAb production approach with potential for clinical translation.
2) Secondary Affibody Tracers:
Smaller fragments of mAbs and engineered proteins that mimic mAbs are also often used in preclinical immuno-PET[3]. These fragments are engineered to retain the affinity of mAbs, but their smaller gives them more favourable pharmacokinetics for PET imaging with short-lived radioisotopes such as fluorine-18. Automated radiosynthesis of smaller antibody fragments with fluorine-18 is challenging due not only to time constraints due to the half-life, but also to the more complex radiochemistry.
Anti-IgG affibody molecules bind to human immunoglobulin G (IgG) subclasses. Fluorine-18 radiolabelled anti-IgG affibody may be used to image antibody-based therapies administered as immuno-oncology agents, akin to a secondary antibody in established immunohistochemistry techniques. This would represent a valuable tool for patient selection and monitoring of treatment response.
3) Tracer Validation
Validation of these methods will involve preclinical comparisons with immunohistochemistry and will be supported by mass spectrometry imaging of the antibodies/fragments within tissues, In collaboration with Kratos (Trafford Park), Matrix Assisted Laser Desorption/Ionisation (MALDI) will be used to investigate the effect of labelling chemistry (using stable isotope equivalents) on the structural integrity of the antibody constructs. MALDI will also be used to image the binding of the antibodies in preclinical tissue sections.

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

[1] M. J. W. D. Vosjan, L. R. Perk, G. W. M. Visser, M. Budde, P. Jurek, G. E. Kiefer, G. A. M. S. van Dongen, Nature Protocols 2010, 5, 739.
[2] I. Verel, G. W. M. Visser, R. Boellaard, M. Stigter-van Walsum, G. B. Snow, G. A. M. S. van Dongen, Journal of Nuclear Medicine 2003, 44, 1271.
[3] O. Morris, M. Fairclough, J. Grigg, C. Prenant, A. McMahon, Journal of Labelled Compounds and Radiopharmaceuticals 2019, 62, 4.



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